Deregulation of signal transduction pathways downstream of receptor tyrosine kinases has been extensively documented in human cancers. The pathway activated phosphotidyl inositol 3-kinase is one that has gain much interest in recent years as a major contributor of tumorigenesis. The biological activity of PI3K is mainly dependent on its ability to phosphorylate the phospholipid PIP2, which results in the generation of the second messenger PIP3. PIP3 can activate a myriad of effectors by serving as a membrane anchor for pleckstrinhomology (PH) domain-containing proteins. The tumor suppressor PTEN, which encodes a dual-specificity phosphatase can oppose PI3K activity by dephosphorylating PIP3 and converting it back to PIP2. It is currently believed that PTEN's tumor suppressing properties are dependent upon this activity. Akt is a serine/threonine kinase that contains a PH domain and is activated by PI3K. It is believed to be a key mediator of PI3K function since it is able to inhibit apoptosis, promote cell growth, and cell proliferation. However, PI3K and Akt loss-of function phenotypes in animal models are not entirely overlapping, suggesting that other PI3K dependent signals are independent of Akt and may be important in PI3K-dependent transformation. We have found that the MAPK JNK, which is known to be involved in apoptosis, differentiation and transformation, can be activated by PTEN loss. Previous studies have demonstrated that JNK is necessary for Bcr-Abl-mediated transformation, and JNK deficient mice are defective in TPA-induced tumorigenesis. Here, we propose to study the role of JNK signaling in tumorigenesis induced by PTEN loss and the mechanistic details of JNK activation in PTEN-deficient cells.